Abstract

A 46 year old man with longstanding type 1 diabetes developed major weight loss and marked deterioration in diabetic control.
He had been persistently injecting insulin into areas of abdominal lipohypertrophy within which hard collagenised fibrous
tissue nodules had developed. Injecting insulin at different sites dramatically improved blood glucose control. Fibrocollagenous
nodules induced by insulin injections have not been previously described. Examination of a further 73 type 1 patients revealed
lipohypertrophy in 44% and hard subcutaneous nodules on two.

Insulin injections can cause a variety of subcutaneous changes, particularly if patients do not rotate sites. This includes
lipohypertrophy, lipoatrophy,1,2 and rarely infections. The extensive use of human insulin has reduced the prevalence of lipoatrophy but lipohypertrophy remains
a significant clinical problem occurring in 27–48% of patients.1–3 Lipohypertrophy can lead to erratic insulin absorption4 and is unsightly.

There are few reports of injection site problems in the recent literature. We report a case of a previously undescribed phenomenon
of bilateral large hard subcutaneous nodules at abdominal wall injection sites. Examination of 73 further patients with type
1 diabetes revealed lipohypertrophy in many cases, two of whom had also developed hard subcutaneous nodules.

CASE REPORT

A 46 year old man with type 1 diabetes of 24 years’ duration presented with an abscess on his scalp. There had been a weight
loss of 11 kg and worsening diabetic control (glycated haemoglobin (HbA1c) increased from 10.6% to 16.5%) despite increased
insulin dose over the past 12 months. He had a history of microalbuminuria, peripheral neuropathy, background retinopathy,
cerebrovascular disease, and hypertension and was taking Human Mixtard 30 insulin 26 units twice daily. For years he had given
all his insulin injections into the abdominal wall. He had bilateral 8 × 8 cm areas of typical lipohypertrophy (see fig 1)
which both contained “woody hard” smooth 4 cm diameter nodules that felt like golf balls. He said he always injected insulin
into these nodules. Biopsies of the core portion of one of the lesions revealed dense hypocellular and hypovascular collagen
with bland looking fibroblasts and foci of necrosis. The appearance was that of collagenous scar tissue. There was no evidence
of amyloid.

Rotation of injection sites, avoiding the nodules and areas of lipohypertrophy was advised. By three months glycaemic control
had improved (HbA1c 9.7%), his weight had increased by 10 kg, and insulin dose had reduced to 38 units daily. The areas of
lipohypertrophy had reduced to 2.5 × 2.5 cm and the nodules were much smaller and softer.

AUDIT OF INJECTION SITES

The injection sites of 73 other consecutive patients with type 1 diabetes (48% male), mean age 31 years, mean duration of
diabetes 13.6 years, and mean HbA1c 9.5% were examined. Thirty three patients (45 %) had not had their injection sites examined
at their last annual review. The majority of patients (42) stated that they rotated insulin injection sites on a regular basis,
while 31 patients tended to stick to one main area, although rotation within that area was reported. The most common sites
for insulin injections were the legs and abdomen. A total of 32 patients (44%) had clinical lipohypertrophy (arms 41%, legs
31%, more than one site 28%). Twenty five were graded as diffuse, five as minor induration, and two patients had hard nodular
lumps within hypertrophied areas (one abdominal and one thigh). One of these patients had very poor diabetic control (HbA1c
14.6%) and recent weight loss and also admitted injecting repeatedly into the hard nodules. There was no significant difference
in HbA1c between those with lipohypertrophy and those without (9.6% v 9.5%). Mean (SD) duration of diabetes was significantly longer in those with lipohypertrophy than those without (17.2 (9.2)
v 11 (7.1) years, p<0.02).

All three patients with hard nodules (including the index case) were currently injecting human insulin.

DISCUSSION

Previous studies of insulin injection sites have not reported discrete large hard nodules of fibrocollagenous scar tissue,
although there is one report of a hard thigh nodule containing amyloid.5 Our audit identified a further two patients with similar hard nodules, both had poor diabetic control (HbA1c 14.4% and 11.1%),
and one had weight loss similar to the index case. It is reasonable to assume that repeated trauma of localised subcutaneous
injections may lead to fat necrosis and then nodules of fibrocollagenous scar tissue. These nodules would not be very vascular
and injecting into them would lead to impaired insulin release and poor diabetic control. In our index patient there was a
marked improvement in glycaemic control and weight gain after rotation of insulin injection sites and the hard collagen nodules
shrank. All three patients with hard nodular lumps admitted to injecting all insulin injections into the nodules mainly due
to habit and comfort despite being previously informed of the importance of rotation of insulin sites. Interestingly the abdominal
nodules were only noticeable to the two patients after a rapid weight loss and were more apparent when standing up. Injection
site lipohypertrophy remains a significant problem in our clinic population with 44% of patients surveyed having some degree
of lipohypertrophy. Previously reported prevalence rates vary from 27%–48%,1,2 with higher rates reported in type 1 diabetes than type 2 insulin treated diabetes.6 As with several previous studies we did not find any significant difference in glycaemic control between those with lipohypertrophy
and those with no lipohypertrophy.1,6 Lipohypertrophy was associated with a longer duration of diabetes and it is possible that some of these patients would have
been initially treated with animal insulins. It is disappointing that nearly half of our patients (45%) had not had their
injection sites examined at the last annual review, although this is recommended.7

Learning points

Lipohypertrophy is a common complication of subcutaneous insulin therapy.

Hard fibrocollagenous nodules can occasionally be found in areas of lipohypertrophy and can be associated with poor diabetic
control.

Patients should be advised to rotate injection sites preferably avoiding the same patch of skin for a month.

Injection sites should be examined at least annually and more frequently if diabetic control deteriorates.

Many of our patients with lipohypertrophy were aware of the importance of rotating insulin injections sites but cited habit
as the main reason they continued to inject into the same area. Avoidance of sites with lipohypertrophy has been shown to
improve glycaemic control,8,9 therefore repeated advice on the organised rotation of insulin sites needs to be built into patient education programmes.10 Persistent injections into areas of lipohypertrophy can lead to fibrocollagenous scar tissue “golf balls” and cause major
deterioration in diabetic control.